1. Field of the Invention
The present invention relates to methods of diagnosing, preventing and treating Alzheimer's disease based on the use of an inhibitor for the binding of amyloid-β to FcγRIIb, and a method of screening the inhibitor. More particularly, the present invention relates to methods of diagnosing, preventing and treating Alzheimer's disease using an inhibitor of the binding between amyloid-β and FcγRIIb, which is selected from the group consisting of an FcγRIIb protein or a variant thereof, an FcγRIIb extracellular domain, an anti-FcγRIIb antibody, a specific peptide and an FcγRIIb-specific siRNA, and a method of screening the inhibitor.
2. Description of the Related Art
About 50-70% of all people having dementia suffer from Alzheimer's disease (hereinafter, referred to simply as “AD”), which is caused by the progressive degeneration of nerve cells in the brain, resulting in the loss of cognitive ability. AD is divided into two forms: familial AD, which has genetic links and runs in families, and sporadic AD, which develops in many people for no obvious reason. AD patients typically have multiple cognitive deficiencies, which are manifested by memory impairment and psychological symptoms such as psychosomatic abnormalities, including increased anxiety and hypersensitivity.
Two pathological hallmarks are seen in the brains of patients who die of AD: senile plaques and neurofibrillary tangles. Senile plaques are extracellular accumulations of proteins and dead cells, and are primarily composed of amyloid-β (Aβ) peptides (Hardy, J. et al., Nat Neurosci. 1:355-358, 1998). The progressive loss of cognitive ability, which is the major pathological feature of AD patients, seems to be caused by the aberrant deposition of Aβ.
Aβ is produced from amyloid precursor protein (APP) through proteolytic cleavage. APP is cleaved by β-secretase (BACE) and γ-secretase, yielding Aβ (Craven, R., Nat Rev. Neurosci. 2: 533, 2001; David, H. S. et al., Nat Rev. Neurosci. 2: 595-598, 2001; Yankner, B. A., Neuron 16: 921-932, 1996; Selkoe, D. J., Nature 399: A23-A31, 1999).
Studies associated with AD to date resulted in the development of preventive and therapeutic agents for AD mainly using agents inhibiting Aβ production, such as secretase inhibitors, or inhibitors of neurotoxicity, such as antioxidants. Current medications for AD include nicotinic receptor agonists, such as ABT-418; muscarinic receptor agonists, such as Xanomeline and YM-976; acetylcholine precursors, such as lecithin and acetyl-L-carnitine; metal chelators, such as desferrioxamine and clioquinol; beta-sheet breakers, such as iAβ5 and iAβ11; antioxidants, such as vitamin E, Ginkgo biloba, melatonin and idebenone; sAPP releasing agents, such as nicotine, acetylcholine and carbachol; β-secretase or γ-secretase inhibitors, such as OM99-1, OM99-2, OM99-3 and Z-VLL-CHO; non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and indomethacin; hormones such as estrogen; vaccines, such as AN-1792; and cholesterol-lowering agents, such as simvastatin and atorvastatin. However, most medications are only marginally helpful in slightly relieving the pathological symptoms of AD or slowing AD progression, or are difficult to apply in practice due to their toxicity. Thus, there remains an urgent need for the development of stable and effective drugs for AD treatment.
Recent AD-associated studies have been focused on the identification of neurotoxic mechanisms of Aβ. Pro-apoptotic genes, such as prostate apoptosis response-4 (Par-4), tau protein kinase 1 (GSK-3β), Calsenilin/DREAM/KChIP3, and cell death-promoting gene 5 (DP5), are shown to be overexpressed or their activities are increased in neuronal cells cultured in the presence of Aβ or neuronal cells from AD patients. The blocking of the functions of the proteins reduces Aβ-induced neuronal death (Guo, Q. et al., Nat. Med. 4:597-562, 1998; Takashima, A. et al., Proc. Natl. Acad. Sci. USA 90:7789-7793, 1993; Jo, D. G. et al., FASEB J. 15:589-591, 2001; Imaizumi, K. et al., J. Biol. Chem. 274:7975-7981, 1999). However, these reports are not sufficient to identify an intracellular signaling pathway for Aβ-induced neuronal toxicity so as to develop AD drugs for preventing Aβ-induced neuronal loss. To date, inhibitors of Aβ-induced neurotoxicity have not been found even in vitro.
An important step to define neurotoxic mechanisms of Aβ is to find a receptor for Aβ on neuronal cells. Many efforts have been made, but no specific receptor for Aβ has been identified yet. Several proteins interacting with Aβ, including receptors for advanced glycation end-product (RAGE) (Arancio, O. et al., EMBO J. 23:4096-4105, 2004) and amyloid-beta binding alcohol dehydrogenase (ABAD) (Takuma, K. et al., FASEB J. 19:597-598, 2005), were reported to be receptors for Aβ. However, such proteins have been shown to serve as cellular cofactors, rather than functioning to fundamentally modulate signal transduction in neuronal cells or neuronal toxicity. Thus, they are not likely to be receptors for Aβ. This is because they were identified not using a knock-out method but through the observation that their overexpression increases signal transduction and neuronal toxicity.
On the other hand, Fcγ receptor IIb (FcγRIIb), expressed on immune cells, has been known to be a receptor having low binding affinity to immunoglobulin G. Individuals having a mutation in the FcγRIIb gene (FcγRIIb[I232T]), leading to abnormal immune responses, are susceptible to autoimmune diseases. Also, the FcγRIIb receptor has recently been known to play a regulatory role in arthritis (Nakamura, A. et al., Biomed. Pharmacother. 58:292-298, 2004). However, the involvement of FcγRIIb in dementia and its potential as a therapeutic target for dementia have not been known.
The inventors of this application found for the first time that FcγRIIb serves as a receptor for Aβ as well as playing an immunoregulatory role. In particular, the present inventors found that FcγRIIb acts as a protein mediating Aβ neurotoxicity and serves as a receptor in an Aβ-initiated toxic signaling pathway, through which FcγRIIb binds Aβ as the first event of the toxic signaling in neuronal cells and transduces the cell death signal into the cells. The present inventors also found that FcγRIIb enhances Aβ deposition, associated with memory impairment in AD, within neuronal cells. Based on these findings, the present inventors further found that an FcγRIIb protein or a variant thereof, an FcγRIIb extracellular domain, an anti-FcγRIIb antibody, an FcγRIIb-specific peptide and an FcγRIIb-specific siRNA suppress neuronal cell death and prevent memory loss in subjects, thereby leading to the present invention.